U.S. patent application number 17/444014 was filed with the patent office on 2021-11-18 for solid state ph sensing continuous flow system.
This patent application is currently assigned to Parker-Hannifin Corporation. The applicant listed for this patent is Parker-Hannifin Corporation. Invention is credited to Srinivas Rao, Steve Roth, Thang Huy Vu.
Application Number | 20210356418 17/444014 |
Document ID | / |
Family ID | 1000005752981 |
Filed Date | 2021-11-18 |
United States Patent
Application |
20210356418 |
Kind Code |
A1 |
Vu; Thang Huy ; et
al. |
November 18, 2021 |
SOLID STATE PH SENSING CONTINUOUS FLOW SYSTEM
Abstract
The present invention relates generally to systems for measuring
pH. In particular, the present invention relates to a continuous
flow system having one or more solid state pH sensors positioned
within a fluid pathway of the system to provide continuous pH
measurement.
Inventors: |
Vu; Thang Huy; (San Jose,
CA) ; Roth; Steve; (San Jose, CA) ; Rao;
Srinivas; (Sunnyvale, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Parker-Hannifin Corporation |
Cleveland |
OH |
US |
|
|
Assignee: |
Parker-Hannifin Corporation
Cleveland
OH
|
Family ID: |
1000005752981 |
Appl. No.: |
17/444014 |
Filed: |
July 29, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15469234 |
Mar 24, 2017 |
11079350 |
|
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17444014 |
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62313607 |
Mar 25, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
G01N 27/302
20130101 |
International
Class: |
G01N 27/30 20060101
G01N027/30 |
Claims
1-15. (canceled)
16. A continuous flow pH sensor housing, comprising: an outer top
surface comprising a threaded opening; an outer bottom surface
opposite the outer top surface; a sidewall comprising an outer
sidewall surface and an inner sidewall surface, said inner sidewall
surface in fluid communication with the outer top surface via the
threaded opening; an inner bottom surface, said inner bottom
surface and said inner sidewall surface defining a fluid pathway;
an inlet port positioned in the sidewall in proximity to, and
spaced apart from, the inner bottom surface and in fluid
communication with the fluid pathway; an outlet port positioned in
the sidewall in proximity to the threaded opening and in fluid
communication with the fluid pathway, such that a distance between
the outlet port and the inner bottom surface is greater than a
distance between the inlet port and the inner bottom surface; and a
pH probe adapter threadedly coupled to the threaded opening and
comprising a central opening configured to selectively receive a pH
sensor such that a distal tip of the pH sensor is positioned
between the inner bottom surface and the inlet port.
17. The system of claim 16, further comprising an upstream fluid
source coupled to the inlet port.
18. The system of claim 17, further comprising a fluid pump
interposed between the upstream fluid source and the pH sensor
housing.
19. The system of claim 17, further comprising an in-line static
mixer interposed between the upstream fluid source and the pH
sensor housing.
20. The system of claim 16, wherein the solid state pH sensor
comprises a plurality of solid state electrodes.
21. The system of claim 20, wherein the plurality of solid state
electrodes are selected from the group consisting of a working
electrode, a reference electrode, a pseudo reference electrode, and
a counter electrode.
22. The system of claim 16, wherein the solid state pH sensor
comprises a probe assembly having an elongated body, a portion of
which is inserted through the central opening.
23. The system of claim 20, wherein the inlet port and the outlet
port define the fluid pathway through the pH sensor housing.
24. The system of claim 23, wherein the fluid pathway maintains a
constant flow of a fluid through the pH sensor housing.
25. The system of claim 23, wherein the solid state pH sensor is
positioned within the pH sensor housing such that the plurality of
solid state electrodes is positioned in the fluid pathway in
proximity to the inlet port.
26. The system of claim 16, wherein the solid state pH sensor
further comprises an analyte insensitive material (AIM).
27. The system of claim 16, wherein the solid state pH sensor
measures pH accurately to within .+-.0.1 pH units.
28. The system of claim 27, wherein the system supports flow rates
from 5 ml/min to 500 ml/min.
29. The system of claim 16, wherein the system provides real-time
pH monitoring under flow conditions.
30. A continuous flow pH monitoring system, comprising: a pH
sensor; a pH sensor housing comprising: an outer top surface
comprising a threaded opening; an outer bottom surface opposite the
outer top surface; a sidewall comprising an outer sidewall surface
and an inner sidewall surface, said inner sidewall surface in fluid
communication with the outer top surface via the threaded opening;
an inner bottom surface, said inner bottom surface and said inner
sidewall surface defining a fluid pathway; an inlet port positioned
in the sidewall in proximity to, and spaced apart from, the inner
bottom surface and in fluid communication with the fluid pathway;
and an outlet port positioned in the sidewall in proximity to the
threaded opening and in fluid communication with the fluid pathway,
such that a distance between the outlet port and the inner bottom
surface is greater than a distance between the inlet port and the
inner bottom surface; and a pH probe adapter threadedly coupled to
the threaded opening and comprising a central opening configured to
selectively receive the pH sensor such that a distal tip of the pH
sensor is positioned between the inner bottom surface and the inlet
port.
31. The system of claim 30, further comprising an upstream fluid
source coupled to the inlet port.
32. The system of claim 30, wherein the solid state pH sensor
comprises a plurality of solid state electrodes.
33. The system of claim 32, wherein the plurality of solid state
electrodes are selected from the group consisting of a working
electrode, a reference electrode, a pseudo reference electrode, and
a counter electrode.
34. The system of claim 30, wherein the solid state pH sensor
comprises a probe assembly having an elongated body, a portion of
which is inserted through the central opening.
35. The system of claim 30, wherein the fluid pathway maintains a
constant flow of a fluid through the pH sensor housing.
Description
RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Patent
Application Ser. No. 62/313,607, entitled SOLID STATE pH SENSING
CONTINUOUS FLOW SYSTEM, filed on Mar. 25, 2016, which is
incorporated herein by reference in its entirety.
BACKGROUND OF THE INVENTION
Field of the Invention
[0002] The present invention relates generally to systems for
measuring pH. In particular, the present invention relates to a
continuous flow system having one or more solid state pH sensors
positioned within a fluid pathway of the system to provide
continuous pH measurement.
Background
[0003] Most conventional pH sensors on the market today utilize an
ion sensitive glass bulb sensitive to pH and an internal reference
electrode. These conventional pH probes require constant
recalibration, the electrodes must be stored in a KCl solution to
keep the porous frit from drying out, and the fragile glass
membrane renders these probes unsuitable for many applications
where pH measurement is required under conditions of high
temperature or pressure. The performance of these pH sensors
decrease over time as the glass membrane may become less sensitive
to ions in a solution.
[0004] Effort has been made to improve the function of the
reference electrode by, for instance, modification of the
electrode-analyte interface (see U.S. Pat. No. 7,276,142) or
replacement of the typically heterogeneous redox couple (e.g.
calomel or silver/silver chloride) with a homogeneous redox couple
(e.g. iodide/triiodide) (see U.S. Pat. No. 4,495,050). These
changes are based on the extension of the potentiometric reference
electrode concept wherein the conventional reference electrode
(CRE) typically comprises two halves of a redox couple in contact
with an electrolyte of fixed ionic composition and ionic strength.
Because both halves of the redox couple are present and the
composition of all the species involved is fixed, the system is
maintained at equilibrium and the potential drop (i.e. the measured
voltage) across the electrode-electrolyte interface of the
conventional reference electrode is then thermodynamically fixed
and constant. The function of the reference electrode is then to
provide a fixed potential to which other measurements, such as pH,
may be compared.
[0005] While these conventional reference electrodes provide a
stable potential, they suffer from many disadvantages. One
disadvantage is the need for an electrolyte of fixed and known
ionic composition and ionic strength, because any change in ionic
composition or strength will result in a shift in equilibrium of
the redox couple, thereby compromising the stability of the
constant potential of the electrode. To preclude a change in
electrolyte composition, the redox system and electrolyte are
typically isolated from the sample under study via a porous frit or
small aperture. This isolation introduces an additional
disadvantage to the conventional reference electrode, namely the
propensity for the frit or aperture to clog, rendering the
electrode useless. These disadvantages are exacerbated by the fact
that the electrolyte is typically an aqueous solution of high salt
concentration, resulting in the requirement that the electrode frit
or aperture must be kept wet to avoid clogging due to salt
precipitation.
[0006] For glass pH probes, a measuring circuit using a solution
ground or other means to boost reference input impedance may be
required to improve stability of the reference electrode in analyte
solutions having certain conductivity properties. Otherwise,
replacing or rejuvenating the reference electrode at more frequent
intervals may be necessary. Following good sampling practices and
using quality instrumentation is normally required to reduce the
flow dependence of these measurements to negligible levels. This
enables closer control of cycle chemistry with resultant increases
in efficiency by reducing corrosion rates and corrosion product
deposition in the system.
[0007] Glass bulb pH probes are further inefficient and unreliable
at measuring pH in continuous flow conditions. As used herein,
"continuous flow conditions" is understood to describe the
uninterrupted flow of a fluid for which measurement of the fluid's
pH is desired. The flow rate at which the fluid bypasses the glass
bulb pH probe determines how long the analyte is actually in
contact with the probe electrodes. In case of glass pH probe,
controlling the flow is an important variable in probe performance
(process time and response time). Further, there are at least three
challenges to consider when measuring pH under continuous flow
conditions, namely, ionization, sampling and sensor effects.
Ionization/Dissociation
[0008] Flow itself does not cause change in ionic concentration.
Under moderate conditions, an analyte under flow experiences no
effect on ionization. In other words, there is no inherent flow
dependence for ionization. However, there can be secondary factors
which effect ionization of an analyte under flow. For example, in
some instances flow may affect sample temperature which in turn
influences ionization. Thus, pH sampling under these conditions
must account for ionization.
Sampling
[0009] Continuous flow systems may include numerous fittings,
crevices, reaction products and deposits which may affect flow
rate, and thereby have a significant effect on the adsorption and
desorption of ions within the system. This is especially true in
continuous flow systems having contaminated sample lines. Thus, the
actual ionic content of a sample fluid may be affected. This type
of phenomenon is commonly observed in capillary tubing of ion
chromatographs, where various ion adsorbing and desorbing is seen
along the length of the tubing. The resulting effect on pH
measurement is increased and variable response times, as compared
to stagnant conditions. Flow rates further affect ion transport,
which further contributes to unreliable pH measurement response
times, especially when combined with the porous structure of glass
bulb pH probes.
Sensor Effects
[0010] Glass pH probe sensors are susceptible to flow dependence
from two basic sources, namely streaming potentials and reference
junction potentials, which occurs between probe's pH measuring and
reference electrodes. Thus, pH measurement with glass probe sensors
provide unreliable measurement under continuous flow conditions due
to flow dependent interference based on the millivolt signal
between these electrodes.
[0011] While pH is unaffected by flowrate, the measurement of pH
with glass probe can be greatly affected by flowrate. Fluid
mechanics, system layout, and glass probe placement may further
affect measurement of pH.
[0012] Further still, fluid pressure may affect pH measurement
since it directly affects the reference junction of a glass pH
probe, which may force trace amounts of process material into the
junction. At very low or very high pH (<4 or >10 pH) this
will have greater effect on pH measurement and could be on the
order of .+-.0.2 pH for large pressure changes glass pH probes
further have challenges with cycling high pressures and flowrates
which cause slight compression and expansion of electrolyte
contents, thereby causing electrolyte dilution or contamination in
the junction, which shortens the life of a pH sensor. High flow
rates or cycling high pressures may further lead to structural
failure of the fragile glass material of traditional pH probes.
[0013] Accordingly, while systems and methods currently exist for
measuring pH under continuous flow conditions, challenges still
exist. The systems and methods of the present invention overcome
these challenges.
SUMMARY OF THE INVENTION
[0014] The Present invention relates generally to systems and
methods for measuring pH under continuous flow conditions.
Specifically, some embodiments of the present invention provide a
continuous flow system having one or more housings for compatibly
receiving and positioning a solid state pH sensor in the fluid
pathway of the continuous flow system, thereby assuring that
measurement accuracy is not compromised by variance in flow rate.
In some instances, the continuous flow system comprises a plurality
of fluid sources at one or more flow rates, wherein the fluid
sources might react with one another to affect a change in pH.
[0015] In some embodiments, the present invention comprises a solid
state pH sensor having an analyte sensitive material (ASM)
covalently bound to a polymer backbone, wherein the ASM comprises
at least one of a quinone, dihydroxy anthraquinone, or an
anthraquinone derivative, as disclosed in PCT/US2011/045385, which
is incorporated herein in its entirety.
[0016] In some embodiments, the present invention further comprises
a solid state pH sensor having a reference electrode comprising an
analyte insensitive material (AIM) comprising at least one of
ferrocene or a ferrocene derivative copolymerized in an acrylamide
or bis-acrylamide network, as disclosed in PCT/US2015/035428, which
is incorporated herein in its entirety.
[0017] In some embodiments, the present invention comprises a solid
state pH meter device having four electrodes, and which is capable
of accurately measuring pH in a continuous flow environment.
[0018] In some instances, the present invention comprises one or
more housings, each housing having a port comprising a solid state
pH sensor, wherein the pH sensor comprises one or more redox active
materials.
[0019] In some instances, the continuous flow system of the present
invention further includes a pseudo-reference electrode (PRE)
comprising a sintered silver-silver chloride wire electrode which
is used in combination with a redox active reference electrode
comprising an AIM and a working electrode (WE).
[0020] In some instances, the continuous flow system of the present
further comprises one or more solid state pH probes comprising an
ASM covalently coupled to a polymer matrix, wherein the polymer
matrix comprises at least one of a poly(vinyl alcohol) (PVA) or
acrylamide matrix material, or an interpenetrating polymer network
(IPN) comprising two or more polymers, as disclosed in
PCT/US2011/45385.
[0021] In some instances, the continuous flow system of the present
invention further comprises one or more solid state pH probes
comprising at least one of an AIM and an ASM polymerized in an
acrylamide network, as disclosed in PCT/US2015/035428.
BRIEF DESCRIPTION OF THE FIGURES
[0022] FIG. 1 shows a schematic view of a continuous flow system in
accordance with a representative embodiment of the present
invention.
[0023] FIG. 2A shows a detailed view of a pH sensor housing of a
continuous flow system in accordance with a representative
embodiment of the present invention.
[0024] FIG. 2B shows a cross-section side view of a pH sensor
housing of a continuous flow system in accordance with a
representative embodiment of the present invention.
[0025] FIG. 3 shows engineered drawings of the pH sensor housing of
FIG. 2, in accordance with a representative embodiment of the
present invention.
[0026] FIG. 4 is a cross-section side view of a pH sensor housing
in accordance with a representative embodiment of the present
invention,
[0027] FIG. 5 is a graph demonstrating longevity for a solid state
S4 Blade pH sensor exposed to Gamma rays at 36-38 Kgray over 50
days in BDH pH 7 with 100 mM NaCl added and run at 37 deg C., in
accordance with a representative embodiment of the present
invention.
[0028] FIG. 6 is a schematic view of an electronics system in
accordance with a representative embodiment of the present
invention.
[0029] FIG. 7 is a schematic view demonstrating the function of an
AIM in a pH probe sensor of a continuous flow system in accordance
with a representative embodiment of the present invention.
[0030] FIGS. 8-13 show various graphs demonstrating pH response of
solid state pH sensors in a continuous flow system under various
flow conditions in accordance with a representative embodiment of
the present invention,
[0031] FIGS. 14-19 show various graphs demonstrating pH response of
solid state pH sensors under static conditions in accordance with a
representative embodiment of the present invention.
[0032] FIG. 20 shows various graphs comparing response times
between solid state pH sensors and traditional glass bulb pH
sensors in a continuous flow system in accordance to a
representative embodiment of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0033] The present invention relates generally to systems for
measuring pH. In particular, the present invention relates to a
continuous flow system having one or more solid state pH sensors
positioned within a fluid pathway of the system to provide
continuous pH measurement.
[0034] Referring now to FIG. 1, a continuous flow system 10 is
shown. In some embodiments, system 10 comprises a fluid source 12,
such as a biological or life science fluidic sample. In some
instances, fluid source 12 comprises a storage container. In some
instances, fluid source 12 comprises a reaction chamber. Further
still, in some embodiments fluid source 12 comprises an upstream
manufacturing process, such as the production of a fluid product
for which pH measurement and/or monitoring is desirable. In one
embodiment, fluid source 12 comprises an upstream manufacturing
process for a foodstuff. In one embodiment, fluid source 12
comprises an upstream manufacturing process for a chemical reagent.
In one embodiment, fluid source 12 comprises a manufacturing
process for a biological material.
[0035] In some embodiments, continuous flow system 10 further
comprises a primary fluid pump 14 whereby to draw fluid from fluid
source 12 through fluid line 16. Fluid pump 14 may comprise any
type of suitable pump. For example, in some embodiments fluid pump
14 comprises a positive-displacement pump, such as a bulk-handling
or metering pump. In other embodiments, fluid pump 14 is positioned
upstream from fluid source 12 and comprises a
nonpositive-displacement pump, such as a centrifugal pump.
[0036] Continuous flow system 10 further comprises a pH sensor
housing 18. In some embodiments, housing 18 comprises an inlet port
22 for receiving an upstream fluid line 30 and an outlet port for
receiving a downstream fluid line 32. Housing 18 further comprises
a probe port 20 configured to selectively receive pH probe 40 in a
fluid tight manner. pH probe 40 is further operably connected to a
computer processor 50 via a data link 52.
[0037] pH probe 40 comprises a plurality of solid state pH sensors
which provide stable pH measurement under various flow rates and
conditions. As used herein, the term "pH sensor" is used to refer
to a functional grouping of electrodes sufficient to generate a
signal that can be processed to generate a reading indicative of
the concentration of an analyte of interest in a solution. These
electrodes may include a "working electrode", a "reference
electrode", a "pseudo reference electrode" or a "counter
electrode", as is commonly understood in the art. In some
instances, pH probe 40 comprises a single surface that is exposed
to the fluid source, wherein the single surface comprises a
plurality of pH sensor electrodes.
[0038] In some embodiments, pH probe 40 comprises a solid state
sensor having a redox active material immobilized on a conductive
substrate, as discussed in PCT/US2015/035428 and PCT/US11/45385. In
some embodiments, pH probe 40 further comprises a handheld
assembly, as discussed in PCT/US2013/029746, which is incorporated
herein in its entirety.
[0039] In some embodiments, pH sensor housing 18 comprises an
internal pH sensor, wherein probe port 20 is absent or otherwise
stopped, and an internal pH sensor is enclosed within pH sensor
housing and positioned within a fluid pathway through pH sensor
housing 18. In some instances, probe port 20 is stopped with a plug
comprising a pH sensor.
[0040] In some embodiments, continuous flow system 10 further
comprises a second fluid source 13 that is coupled to upstream
fluid line 30 via secondary upstream and secondary downstream fluid
lines 17 and 31, respectively. In some instances, system 10 further
comprises a secondary fluid pump 15. For configurations comprising
both first and second fluid sources 12 and 13, system 10 may
further comprise an in-line static mixer 34 positioned downstream
of location at which the flow from first and second fluid sources
12 and 13 converge.
[0041] In some embodiments, primary fluid pump 12 and secondary
fluid pump 13 pump their respective fluids at equal flow rates. In
some embodiments, primary fluid pump 12 pumps first fluid source 12
at a first flow rate, and secondary fluid pump 13 pumps second
fluid source 13 at a second flow rate, wherein the first flow rate
is greater than the second flow rate.
[0042] Continuous flow system 10 may further comprise a second pH
sensor housing 55. In some instances, second pH sensor housing 55
is positioned downstream from pH sensor housing 18. In other
instances, second pH sensor housing 55 is positioned upstream from
pH sensor housing 18. Further, in some instances continuous flow
system 10 comprises more than two pH sensor housings (not shown).
Second pH sensor housing 55 further comprises an inlet port 52, and
outlet port 54, and a probe port 56, wherein probe port 56 is
configured to receive a second pH probe 60.
[0043] In some instances, pH sensor housing 18 is spaced from
second pH sensor housing 55 by a distance predetermined to detect a
change in pH of a fluid source. In some instances, a manufacturing
process or treatment is interposed between pH sensor housing 18 and
second pH sensor housing 55. For example, in some instances
secondary downstream fluid line 31 converges with downstream fluid
line 30 at a point downstream from pH sensor housing 18. Thus,
second pH sensor housing 55 is positioned to measure the pH of the
combined fluid sources 12 and 13.
[0044] The solid state components of the present invention can be
stored dry or wet and require no maintenance or calibration. The
solid state reference electrode comprises a solid material that is
not subject to changes in potential based on diffusion. Further,
the analyte insensitive material (AIM) adjusts for changes in
potential of the solid reference electrode, thereby eliminating the
need for calibration. Because all components of the pH sensor are
solid, contamination of process flow by leaching is reduced.
Further, in-line pH sensors can be sterilized by autoclave or Gamma
treatment for processes requiring sterile environments.
[0045] Referring now to FIGS. 2A, 2B and 3, a solid state pH meter
40 is shown inserted within pH sensor housing 18 of the instant
invention. In some embodiments, pH sensor housing 18 comprises a
probe port 20 having a set of threads 21 configured to receive a
matching set of threads 41 on an outer surface of a probe adapter
43. Probe adapter 43 generally comprises an elongated body having a
central opening 23 configured to selectively receive pH probe 40.
In some instances, central opening 23 further comprises one or more
sealing members 25, such as an O-ring, which forms a fluid tight
seal between central opening 23 and the outer surface of pH probe
40. Sealing member 25 thus prevents passage of fluids through
central opening 23. In some instances, sealing member 25 is
positioned such that sealing member 25 is compressed as probe
adapter 43 is threaded into probe port 20. Thus, the compressive
force between sealing member 25 and the outer surface of pH probe
40 is increased as probe adapter 43 is threadedly inserted into
probe port 20. In some embodiments, probe adapter 43 further
comprises a locking nut 47 that is tightened against the top
surface of pH sensor housing to prevent premature disengagement of
the adapter from the port. In some instances, probe adapter 43
further comprises a cap 49 having an outer surface to enable
threaded insertion of the adapter into probe port 20. In some
embodiments, sealing member 25 is interposedly positioned between
the outer surface of pH probe 40 and an inner surface of cap 49. In
some instances, a tip portion of pH probe 40 is threaded so as to
be directly coupled to the threads of probe port 20, in a fluid
tight manner, without requiring probe adapter 43 (not shown).
[0046] Tip 45 of pH probe 40 further comprises a pH sensor that
extends distally from the body of the pH probe and is positioned
within fluid pathway 19 of pH sensor housing 18 when pH probe 40 is
coupled thereto. pH sensor housing 18 comprises an inner diameter
selected to accommodate placement of pH sensor tip 45 without
occluding or otherwise blocking fluid pathway 19.
[0047] In some embodiments, the inlet port 22 and outlet port 24 of
pH sensor housing 18 are offset, such that fluid enters towards the
bottom of the housing and exits towards the top of the housing.
This method of flow prevents entrapment of air bubbles that may
otherwise be retained against pH sensor 45 as a result of aberrant
flows caused by top filling housing 18. This method of flow further
maintains constant contact between the fluid and pH sensor 45,
regardless of flow rate disturbance or fluctuation. In some
instances, the fluid pathway through probe port 20 is devoid of
right angles, thereby preventing aberrant flows or stagnation which
may cause localized areas of increased ion concentrations.
[0048] Referring now to FIG. 4, in one embodiment pH sensor housing
118 comprises an elongated body having a plurality of individual pH
sensors 145 positioned along the length of housing 118. Each pH
sensor is spaced apart from an adjacent pH sensor. An active
surface of each sensor is positioned within the fluid pathway 119
in order to make contact with a fluid source moving there through.
In some instances, the exposed surface area of one or more of the
plurality of sensors 145 is increased by moving the sensor further
into the fluid pathway 119. In some instances, the plurality of
sensors 145 are positioned flush with the inner wall surface of pH
sensor housing 118. In some instances, the plurality of sensors 145
are recessed within the inner wall surface of pH sensor housing
118. Plurality of sensors 145 further comprise connector leads 152
that are collectively or individually connected to one or more
computer processors 50.
[0049] In some embodiments, each sensor comprises a unique function
that is used in combination with one or more of the remaining
sensors to collectively detect an analyte in the fluid source. In
some embodiments, pH sensor housing 118 comprises two or more
replicate sensors. Further, in some instances a continuous flow
system 10 comprises a plurality of pH sensor housings 118, wherein
two or more of the housings comprise an identical set of pH
sensors. In other embodiments, a continuous flow system 10
comprises a plurality of pH sensor housings 118, wherein two or
more of the housings comprise a unique set of pH sensors.
[0050] In some instances, a pH probe and continuous flow system of
the present invention is designed in a
"Made-to-fit-the-application" format, which may be customized to
accommodate a variety of applications, as discussed in U.S.
Provisional application Ser. No. 62/198,580, which is incorporated
herein in its entirety.
[0051] In some embodiments, pH probe 40 comprises great stability
and works well within the accuracy range of .+-.0.1 pH units. pH
probe 40 is further configured to work without failure for more
than 21 days. In some instances, pH probe 40 can withstand gamma
radiation used for sterilization purposes up to 45 KGy, without
failure. Accordingly, pH probe 40 is compatible for use in various
Biotech industry applications needing special sterilization
techniques. In some embodiments, pH probe 40 does not show any
change in performance after sterilization, as shown in FIG. 5.
[0052] In one embodiment, computer processor 50 utilizes SWV
electronics to multiplex between the inputs from the working
electrode (WE) and the internal electrode (IE) of one or more pH
sensors. The WE and IE inputs are electrically equivalent and are
in common with the reference electrode/pseudo reference electrode
(RE/PRE) and counter electrode (CE) circuits. The operation of this
system is illustrated in the block diagrams shown in FIG. 5.
[0053] With continued reference to FIG. 6, the differentiating
feature of the potentiostat circuitry (Blocks 1 to 9) is a
multiplexer (3), used to select either the ASM or AIM electrodes.
The transimpedance amplifier (4), analog-digital converter (ADC)
(5), Reference Electrode (6), digital-analog converter (DAC) for
generating the square wave excitation (7), and Difference Amplifier
(8) that drives the Counter Electrode (9) are common to both the WE
the IE.
[0054] The SWV operating parameters, including voltage scan (or
sweep) range, pedestal height, equilibration time, and dwell time
(i.e. rest time between sequential voltage scans), are
independently adjustable for the WE and IE. In one embodiment, the
same SWV circuit is used to monitor the WE and IE sequentially.
[0055] The overall time sequence of WE and IE scan is diagrammed in
FIG. 7. Arrows represent grouping of scans, or repetitions,
occurring at regular intervals set at independent dwell times.
[0056] The scan parameters are optimized for each electrode.
Statistics, i.e. peak potential averages and standard deviations of
a series of repetitions of scans, can be kept separately for the WE
and IE so that the results from these electrodes can be
independently analyzed.
EXAMPLES
Example 1: pH Response in Continuous Flow System
[0057] Referring now to FIGS. 8-13, various experiments were
conducted to test pH response of solid state pH probes under
continuous flow conditions. A typical sample used was 100 mM
phosphate buffer with 1% W/V BSA. A second solution, 100 mM HCl was
used to induce changes in pH. Each solution was introduced at
different flow rates into a common 1/4 inch ID tube equipped with
an in-line static mixer using two separate pumps. This allowed for
independent rate adjustments of each solution. Flow rate of the
sample (phosphate/BSA) was studied across a range of 5 to 468
mL/min. Flow rate of the HCl was adjusted to create three common
Phosphate/HCl ratios for each Phosphate flow rate studied.
[0058] Table 1 shows the estimated flow rates of both pumps and the
summed flow rate running through the common tube across a range of
5 to 125 mL/min. The final column in table 1 shows how much time is
required to fill the chamber from the static mixer based on flow
rate.
TABLE-US-00001 TABLE 1 Study Design Flow Rate Flow Rate Time in
Minutes (mL/Minute) (mL/Minute) Total Flow to fill Run
Phosphate/BSA HCl mL/Minute chamber 1 1-1 5 0 5 2.00 1-2 5 0.172
5.17 1.93 1-3 5 0.401 5.40 1.85 1-4 5 0.572 5.57 1.80 2-1 25 0
25.00 0.40 2-2 25 0.859 25.86 0.38 2-3 25 1.659 26.66 0.37 2-4 25
2.358 27.36 0.36 3-1 75 0 75.00 0.13 3-2 75 2.403 77.40 0.129 3-3
75 4.92 79.92 0.125 3-4 75 7.051 82.05 0.121 4-1 125 0 125 0.08 4-2
125 4.006 129.40 0.077 4-3 125 8.195 133.20 0.075 4-4 125 11.790
136.79 0.073
[0059] Table 2 shows the estimated volumes at certain points along
the flow path. Graphs of these results are shown in FIGS. 8-12.
Triplicate results for 25 mL/min are shown in FIG. 10.
TABLE-US-00002 TABLE 2 Volumes along pathway From Static Mixer
Volume in mLs To chamber 1 with the first probe 6 End of chamber 1
with the first probe 10 To chamber 2 with the second probe 12 To
end of chamber 2 with the second probe 36
[0060] For this example, a continuous flow system 10 according to
FIG. 1 was provided, wherein pH probe 40 was subject to flow
conditions, and second, downstream pH probe 60 was used to verify
pH of the final blend following mixing in static mixer 34. It was
found during the course of the study that the pH probe 60 was
subject to slow changes in pH after each change in HCl flow. This
is likely due to delay in fully replacing the previous sample due
to the large box shaped chamber 2. Only chamber 1 data is discussed
herein.
[0061] Solid state probes demonstrated good response and accuracy
in flow applications across a flow rate of 5 to 500 ml per minute
without compromising accuracy, as shown in FIGS. 8-13. Sensor to
sensor variability was determined to be within .+-.0.1 pH units per
the target accuracy specification. Using factory calibration, four
solid state probes measured all flow samples within .+-.0.05 pH
units of a freshly calibrated glass pH meter. The experiment matrix
was filled in, according to Table 1 and different flow rates were
used to check the accuracy and precision of solid state pH probes.
The probes were checked under flow first and then crosschecked for
their performance in Static conditions for comparison purposes. The
probes maintained their accuracy as mentioned in the above
paragraph.
[0062] Measurement of pH was responsive and accurate. At each acid
rate change the sensor equilibrated within 1-2 minutes. The time to
fill pH sensor housing 1 from the static mixer was estimated at 2
minutes at a flow rate of 5 mls/minute, (Table 1 and FIG. 8). The
sensor responded immediately to changes in pH of the solution based
on flow rate and volume to fill the pH sensor housing or port.
[0063] The initial "no acid" condition showed drift of 0.06 pH
units in the first 3 minutes of measurements. This is likely
related to the pH sensor housing or port filling during the initial
part of the run. As the pH sensor housing or port achieved full
volume, the sensor measured accurately. This delayed effect was not
observed in the remaining runs as the pH sensor housing or port was
full after the initial run.
[0064] With reference to FIGS. 9 and 10, the data demonstrated
quick response and accuracy with 25 mL/Minute flow rate. At each
acid rate change the sensor responded within 15-30 seconds. Time to
fill pH sensor housing 1 is estimated at 20 seconds, so response
time is within 10 seconds. Data demonstrates probes are well within
.+-.0.1 target.
[0065] The first acid rate addition was erroneously set low (1 RPM
used vs required 3.75 RPM). The pH change was therefore smaller
than expected. Midway through the first acid addition data, the
acid flow rate was corrected. The erroneous acid flow rate
demonstrates that solid state pH sensor technology is responsive to
smaller changes in pH then called out in the study.
[0066] Referring now to FIG. 11, the data demonstrated quick
response and accuracy with 75 mL/Minute flow rate. Response is seen
immediately at all acid/albumin ratios.
[0067] Referring now to FIG. 12, the data demonstrates quick
response and accuracy with 125 mL/minute flow rate. The results do
appear slightly noisy however very small differences are observed
with no trend.
[0068] With reference to FIG. 13, the data demonstrates steady pH
readings at flow rates of 228 and 468 mL/min.
Example 2: Static pH Measurements of Solid State pH Probes
[0069] Referring now to FIGS. 14-19, various experiments were
conducted to test pH response of solid state pH probed under static
conditions. Static samples were collected at each flow rate from
the continuous flow experiments discussed above. Each static sample
was tested with solid state and traditional glass bulb pH meters.
The static pH measurements were then compared to the continuous
flow pH measurements. With reference to FIGS. 14-18, the static pH
measurements agree within .+-.0.05 pH units of the continuous flow
pH measurements.
[0070] Referring to FIG. 19, static testing of the same continuous
flow samples was conducted using a Senova S4 Blade. The probe was
run continuously with no rinsing of the probe between samples. The
probe was placed into each sample directly, and washed between
samples by swirling the probe in fresh water. The results of this
test demonstrate the quick response of the solid state pH sensors
when placed into each new sample, with accuracy within .+-.0.1 of
the target.
Example 3: Response Time Vs Glass pH Probes-Under Non-Flow
Condition (Static Condition)
[0071] Referring now to FIG. 20, response time of both solid state
and hybrid probes were established empirically based upon titration
of hydrochloric acid into a flow process. The hydrochloric acid
addition reduces pH and it was found that both probe types response
time was limited by scan rate only. The response time for the solid
state was less than one minute at the start of a run and 15 seconds
thereafter. The hybrid probe showed similar results. Glass probes
were tested and found not to give valid pH readings, as no change
was observed in pH upon addition of hydrochloric acid. It was
determined that glass probes do not accurately measure pH in flow
conditions.
[0072] Connective slope points either increasing in positive
direction or decreasing in negative direction indicates that
millivolts are changing in single direction. After achieving the
required equilibration, the slope points will approach the
zero-slope line which means the stability point is reached. As
shown in the above plots solid state pH sensor slope line
approaches the zero-slope line very fast and the total variation is
less than .+-.0.15 mV around the zero-slope line. Measurements of
pH will change 0.1 units with a shift of 6 millivolts, so the
response time is immediate based on accuracy. Millivolts are
plotted for Senova probes (left side range axis) with the total
range shown being .+-.0.1 pH units or 12 mV.
Example 4: Food and Beverage Industry
[0073] A continuous flow solid state pH monitoring system in
accordance with the present invention is used to monitor the pH of
various food or beverage ingredients, or final products during a
manufacturing process. These products may include water, juices,
juice blends, baby foods, fruit and vegetable purees, canned foods,
packaged foods, fresh foods, and processed foods. In one instance,
a plurality of continuous flow solid state pH monitoring systems is
located throughout a manufacturing plant to monitor various
components of a final food or beverage product. In one instance, a
plurality of continuous flow solid state pH monitoring systems are
located at various stages of a manufacturing process to monitor the
pH of a food or beverage product at various points of development
and/or completion.
Example 5: Life Sciences and Pharmaceutical Industry
[0074] A continuous flow solid state pH monitoring system in
accordance with the present invention is used to monitor pH of
various life science and/or pharmaceutical materials in a
laboratory setting, or as part of a manufacturing process. The
materials may include water, buffering agents, chemicals, cell
cultures, lysates, growth medium, reagents, analyte solutions,
vaccines, liquid medicinal preparations, excipients, biologics,
eluents, urine, and blood. In one instance, a plurality of
continuous flow solid state pH monitoring systems are located
throughout a laboratory or manufacturing plant to monitor various
components of a final life science or pharmaceutical material or
product. In one instance, a plurality of continuous flow solid
state pH monitoring systems is located at various stages of a
manufacturing process to monitor the pH of a life science or
pharmaceutical product at various points of development and
completion.
[0075] The present invention may be embodied in other specific
forms without departing from its structures, methods, or other
essential characteristics as broadly described herein and claimed
hereinafter. The described embodiments are to be considered in all
respects only as illustrative, and not restrictive. The scope of
the invention is, therefore, indicated by the appended claims,
rather than by the foregoing description. All changes that come
within the meaning and range of equivalency of the claims are to be
embraced within their scope.
* * * * *